Natural History of Bone Metabolism and Bone Mineral
Density in Children With Inflammatory Bowel Disease
Background: In children with inflammatory bowel disease (IBD)
it is not known whether reductions in bone mineral density (BMD)
are a consequence of bone turnover alterations and if BMD im-
proves with treatment.
Methods: In a cohort of children with IBD, we prospectively
measured indicators of bone remodeling, body mass index (BMI),
disease activity, intact parathyroid hormone, serum IL-6, and insu-
lin-like growth factor-I at diagnosis and then every 6 months for 2
years. BMD was determined annually using dual x-ray absorptiom-
etry (DXA). BMD Z-scores were calculated using height/age. Base-
line measurements and calcium intake were compared with a group
of age- and sex-matched healthy children.
Results: We observed that at diagnosis total body BMD Z-score
(mean ? SD) was ?0.78 ? 1.02 for Crohn’s disease (CD, n ? 58),
?0.46 ? 1.14 for ulcerative colitis (UC, n ? 18), and ?0.17 ? 0.95
for control (CL, n ? 49) (P ? 0.01, CD versus CL). In CD, a BMD
Z-score ??1.0 was associated with lower BMI and higher serum
IL-6. Patients with CD and UC had low bone turnover. Activation of
bone formation paralleled clinical improvement, but BMC gain was
less than expected over the 2-year study period, especially in CD.
Prednisone use did not correlate with low BMD.
Conclusions: Decreased bone turnover occurs in children newly
diagnosed with IBD. Although indicators of osteoblast activity in-
crease with clinical improvement, bone mineral accrual does not
accelerate. Children with low BMI may be considered for BMD
screening, since they are at risk for low bone mass.
(Inflamm Bowel Dis 2007;13:42–50)
Key Words: Crohn’s disease, ulcerative colitis, bone density, chil-
dren, bone formation
(IBD) and its treatment in both children and adults.1–3Most,
but not all, data suggest that patients with Crohn’s disease
(CD) are at greater risk than those with ulcerative colitis
(UC).4–6In children, IBD may interfere with the attainment
and maintenance of peak bone mass, which is the most
important determinant of lifelong skeletal health.7IBD may
affect normal bone modeling and remodeling, resulting in
decreased bone formation and/or increased bone resorption.
Most reports in adults with IBD suggest that bone loss results
is due to increased bone resorption,8–11while others have
reported decreased bone formation relative to bone resorp-
tion.12In developing children it is likely that IBD primarily
affects bone formation and modeling, but this has not been
Previous studies of bone densitometry have been per-
formed in children and adults with long-standing established
disease already treated with drugs, such as corticosteroids,
that by themselves can affect bone metabolism.13Moreover,
many studies have included postmenopausal women, who are
expected to lose bone under normal circumstances due to
bone resorption by osteoclasts, without a compensatory in-
crease in bone formation by osteoblasts.7These limitations
make it difficult to establish the direct contribution of intes-
tinal inflammation to bone loss.
Taking into account the limitations of previous work,
we designed a 2-year prospective observational study in
newly diagnosed children with IBD to observe the character-
istics and progression of bone metabolism and its correlates.
We chose to study our patients from the time of diagnosis to
examine the specific impact of IBD on bone function and
bone mass without the influence of drug therapy. We then
followed these children to gain insight into the natural history
of their bone metabolism, identify clinical and serum markers
that may guide the decision of whom to screen for low bone
mineral density (BMD), and define mechanisms by which
IBD affects bone mass in newly diagnosed children.
ecreased bone mineral density is increasingly recog-
nized as a complication of inflammatory bowel disease
Received for publication May 00 2006; accepted September 00 2006.
From the *Connecticut Children’s Medical Center, Hartford, Connecticut,
and the University of Connecticut School of Medicine, Farmington, Con-
necticut;†Division of Rheumatology, Department of Medicine, Sunnybrook
and Women’s College Health Sciences Centre, and Department of Health
Policy, Management and Evaluation, University of Toronto;‡The Hospital
for Sick Children and the University of Toronto, Toronto, Ontario, Canada.
Supported by a Senior Research Award of the Crohn’s & Colitis Foun-
dation of America, the Crohn’s & Colitis Foundation of Canada, and the
University of Connecticut Health Center General Clinical Research Center
NIH grant M01RR06192.
Reprints: Francisco A. Sylvester, MD, Connecticut Children’s Medical
Center, Division of Gastroenterology & Nutrition, 282 Washington St.,
Hartford, CT 06106 (e-mail: email@example.com)
Copyright © 2006 Crohn’s & Colitis Foundation of America, Inc.
Published online in Wiley InterScience (www.
Inflamm Bowel Dis ● Volume 13, Number 1, January 2007
MATERIALS AND METHODS
Children up to 17 years of age with newly diagnosed
IBD and no other comorbidities were recruited at the Con-
necticut Children’s Medical Center (Hartford, CT) and at the
Hospital for Sick Children (Toronto, Ontario, Canada) from
1999–2002. Healthy children of similar age were recruited in
Hartford, Connecticut, to serve as a control group. Only
Caucasian children were included in the analysis, due to
known significant differences in BMD with other ethnicities.
The healthy children were enrolled at the office of a local
pediatrician by a study nurse at the time of routine health
visits and had no known comorbidities. Control children with
body mass index (BMI) Z-score ?5th percentile and/or
height ?5th percentile were excluded from the analysis.
IBD was diagnosed using standard clinical, laboratory,
radiologic, and endoscopic criteria.14At the time of diagnosis
and at 1 and 2 years after diagnosis, children with IBD had a
clinical evaluation, including determination of disease loca-
tion, completion of the pediatric CD activity index (PC-
DAI),15or the Truelove and Witts activity score for UC,16
assessment of Tanner stage, and calcium intake using a 3-day
food diary. BMD of the lumbar spine (L2–L4) and total body
was obtained using a Lunar densitometer (Lunar DPX-L, GE
Lunar Corp., Madison, WI), with pediatric software v. 1.5h.
A spine phantom was used for quality control, with a coef-
ficient of variation (CV) for the spine of 0.78% and for total
body 0.72%. Values for BMD were expressed in g/cm2. The
observed values were compared to pediatric normative data
obtained using the same type of densitometer.17Z-scores
were determined by subtracting the mean height age- and
sex-specific BMD from the measured BMD, and the result
divided by the normative standard deviation. Mild reduction
in BMD was arbitrarily defined as Z-score ??1 from either
total body or lumbar spine and moderate-to-severe decrease
in BMD as Z-score ??2 from either site. BMD Z-scores
were also calculated based on bone age for each patient. Bone
age was obtained by the method of Greulich-Pyle and deter-
mined by a pediatric radiologist at each site.18We recorded
the cumulative prednisone dose (mg) in children with IBD
Blood and urine samples in the children with IBD were
obtained at diagnosis and at 6-month intervals for 2 years.
Samples were collected prior to diagnostic endoscopy in the
early morning and the second void was collected. Markers of
bone turnover were measured in these samples. Parameters of
bone formation included serum osteocalcin (detected by en-
zyme-linked immunosorbent assay [ELISA], CIS Bio Inter-
national, France), bone alkaline phosphatase (BAP), and car-
(measured by ELISA, Metra Biosystems, Mountain View,
CA). Markers of bone resorption were urinary N- and C-
telopeptides of collagen (NTX and CTX, respectively), and
deoxypyridinoline (DPD) (ELISA, Ostex, Seattle, WA). Se-
rum intact parathyroid hormone (iPTH), and total insulin
growth factor I (IGF-I) levels were measured by kits from
Diagnostic Systems Laboratories (Webster, TX). Serum in-
terleukin 6 (IL-6) was measured as a marker of disease
activity (R&D Systems, Minneapolis, MN). All of the above
measurements were performed at the core laboratory of the
General Clinical Research Center at the University of Con-
necticut Health Center (Farmington, CT). We also measured
serum 25-hydroxy vitamin D levels to assess vitamin D status
(Esoterix Endocrinology, Calabasas Hills, CA, using a com-
petitive protein binding assay after column chromatography).
Data for the healthy control children were collected
only at entry to the study. This included characteristics such
as age, gender, Tanner stage, BMI, height age, bone age,
calcium intake, BMD, and parameters obtained from the
blood and urine samples collected at a special study visit.
Control subjects with height or BMI Z-scores ?5th percentile
for age and sex were excluded from the analysis, so that
control growth values were within 2 SD of the normal mean
Whole blood was spun at 5000g for 10 minutes in a
serum separator tube (Corvac, Kendall Co., Mansfield, MA).
Serum was distributed in 200-?L aliquots in cryovials (Hardy
Diagnostics, Santa Maria, CA) and frozen at ?70°C until
used. All laboratory markers were measured by the core
laboratory of the General Clinical Research Center at the
University of Connecticut Health Center, except for serum
25-OH vitamin D (Esoterix Endocrinology). Urine was col-
lected in a sterile cup. The second morning void was usually
collected. Urine was then transferred to 2 cryovials of 2 mL
each and frozen at ?70°C until used.
This natural history study was not specifically designed
to test hypotheses but rather to observe and describe differ-
ences that could aid in developing future studies. The IBD
sample size was a feasible number of patients to study in the
time available for accrual and follow-up. Differences be-
tween study groups for continuously distributed variables
were evaluated using analysis of variance, followed by mul-
tiple comparisons tests or t-tests. Categorical variables were
analyzed with exact tests. Repeated measures analysis of
variance was used to assess changes over time. Comparison
of Z-scores based on height age and bone age was done using
paired t-tests. When appropriate, statistical significance of
findings was corroborated using nonparametric analogs.
Summary statistics presented are mean ? SD or frequency
and percent. Natural log transformation of BMC and height
Inflamm Bowel Dis ● Volume 13, Number 1, January 2007Bone Metabolism and BMD in Children With IBD
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